To understand the effect of naturally occurring mutations in the lipopolysaccharide of Neisseria meningitidis, henceforth referred to as lipoologosaccharide (LOS), on virulence and natural protection against meningococcal disease, a series of studies were conducted. LOS variants were obtained from three different N. menigitidis strains, two group B and one group C. Changes from serum resistant (SR) to serum sensitive (SS) were found among the isogeneic variants. The variants were characterized as to their LOS immunotype, for presence of lacto- N-neotetrose, and reactivity of isolated outer membranes from the variants with four different normal human sera. We found that changes from SR to SS were associated with changes in immunotype. The wild type group C strain, BB-305, had immunotypes L1,2 and L3,7,9, while the SS variant V1 had only L1,2. Another deeper rough SS variant V2 lacked all these immunotype epitopes. The wild type of a group B strain, BB-1, was resistant in 2 of the 4 sera, and had immunotype epitopes L3,7,9, while the SR variant V1 was immunotype L8. The group B strain 44/76 wild type was L3,7 and was SR. A variant of 44/76 became L8, but remained SR. The monoclonal antibodies My-28 and TIB-189 recognize lacto-N-neotetrose (paragloboside), present on many human tissues and in meningococcal LOS. The structure may play a role in meningococcal virulence. Only wild types of BB-305 and 44/76 expressed this epitope. LOS from the strains were treated with neuraminidase to remove terminal sialic acid. These studies suggested that siaylation does not appear to be related to the observed SR to SS changes. Additional studies with neuraminidase treatment and antibody measurements by ELISA are continuing.